Cellular senescence is a form of irreversible growth arrest, originally described for end-stage proliferative cells in culture, but known to be induced by several stimuli such as DNA damage, oxidative stress, chemotherapy and excess of mitotic stimuli such as oncogenic activation (Serrano et al 1997; Campisi 2001; Schmitt et al 2002). Cells enter in a stage of irreversible arrest, showing distinctive features, including enhanced beta-galactosidase activity and increased expression of key mediators including p53, promyelocitic leukemia protein (PML), p16INK4a and p19Arf (Serrano et al 1997; Narita et al 2003; Sharpless et al 2004). Although mostly studied in vitro, cellular senescence has been correlatively linked to the aging process at the level of the whole animal, thus implicating many of the factors that regulate senescence as contributing to organism aging (Sharpless and DePinho 2004, Campisi 2005).
All senescing cells undergo profound changes in gene expression. Comprehensive gene expression profiling has identified genes in cell cycle, insulin growth factor, interferon, MAP kinase and oxidative stress pathways as consistently dysregulated during cell senescence. Altered gene expression gives rise to the senescent phenotype, and is well established as part of the mechanisms and pathways that activate the senescence program in cells. However, the factors responsible for the alterations of gene expression during senescence remain elusive.
MicroRNAs (miRNAs) are key modulators of gene expression in various biological and pathological processes. Changes in miRNA expression levels occur in cellular senescence and organism aging (Grillari et al 2010; Hackl et al 2010), and have been linked to changes in levels of mRNAs that are putative targets of specific miRNAs (Lafferty et al 2009; He et al 2007; Maes et al 2009). Several studies have identified specific sets of miRNAs up-regulated in fibroblasts replicative senescence (Faraonio et al, 2012; Dhahbi et al, 2011; Yong Wang et al, 2010).
It is thus desirable and important to provide products or active agents which prevent, reduce or even inhibit the cellular senescence, particularly the fibroblast senescence.
The present invention thus provides a method for identifying such useful agents.